A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response:: The PPARα-null mouse as a model of fatty acid oxidation disorders
A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response:: The PPARα-null mouse as a model of fatty acid oxidation disorders
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DOI：
10.1073/pnas.96.13.7473
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发表时间：
1999-06-22
影响因子：
11.1
通讯作者：
Kelly, DP
中科院分区：
文献类型：
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作者：
Leone, TC;Weinheimer, CJ;Kelly, DP
我们假设脂质激活转录因子过氧化物酶体增殖物激活受体 cu (PPAR α) 在细胞对禁食的代谢反应中起着关键作用。短期饥饿导致肝脂肪变性、心肌脂质积累和低血糖，而缺乏 PPAR α (PPAR α(-/-)) 的成年小鼠生酮反应不足，这种表型与具有遗传性基因的人类具有显着的相似性。线粒体脂肪酸氧化酶缺陷。在 PPAR α(+/+) 小鼠中，禁食诱导编码关键线粒体（中链酰基辅酶 A 脱氢酶、肉碱棕榈酰转移酶 I）和线粒体外（酰基辅酶 A 氧化酶、细胞色素 p450 4A3）酶的 PPAR α 靶基因的肝脏和心脏表达。与此形成鲜明对比的是，在 PPAR α(-/-) 小鼠中，大多数 PPAR α 靶基因的肝脏和心脏表达并不是由禁食诱导的。这些结果明确了 PPAR α 在禁食转录调节反应中的关键作用，并将 PPAR α(-/-) 小鼠鉴定为潜在有用的人类脂肪酸利用先天性和后天性异常的小鼠模型。
We hypothesized that the lipid-activated transcription factor, the peroxisome proliferator-activated receptor cu (PPAR alpha), plays a pivotal role in the cellular metabolic response to fasting, Short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPAR alpha (PPAR alpha(-/-)), a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In PPAR alpha(+/+) mice, fasting induced the hepatic and cardiac expression of PPAR alpha target genes encoding key mitochondrial (medium-chain acyl-CoA dehydrogenase, carnitine palmitoyltransferase I) and extramitochondrial (acyl-CoA oxidase, cytochrome p450 4A3) enzymes. In striking contrast, the hepatic and cardiac expression of most PPAR alpha target genes was not induced by fasting in PPAR alpha(-/-) mice, These results define a critical role for PPAR alpha in a transcriptional regulatory response to fasting and identify the PPAR alpha(-/-) mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization.